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Objective: Surgical correction of adult spinal deformity (ASD) is associated with a high rate of hardware complication that can be challenging to predict. Hardware integrity and alignment after surgery are typically followed with standing radiography, where pedicle screw loosening may be incidentally identified but the clinical significance of which is often unclear. This study aimed to identify the incidence and implications of pedicle screw loosening at the upper instrumented vertebra (UIV) after surgical correction of ASD., Methods: A single-institution retrospective analysis was performed on a cohort of 217 patients who underwent long-segment fusion with pelvic fixation for correction of ASD between September 2013 and November 2021. Cases with a minimum 1-year follow-up were included. UIV pedicle screws were graded on radiographs for evidence of loosening with a 0- to 3-point scale: 0, no loosening; 1, lucency within screw threads; 2, lucency around screw threads; and 3, screw dislodgment/backout. Need for hardware revision surgery was assessed as the primary outcome. Patient-reported outcome measures (PROMIS and Oswestry Disability Index scores) were assessed as secondary outcomes among the patients with available scores., Results: Low-grade UIV screw loosening (grade 1) was identified in 37 patients (17.1%), and high-grade UIV loosening (grade 2 or 3) was identified in 23 patients (10.6%). Low-grade UIV loosening was not associated with eventual need for hardware revision (OR 0.52, 95% CI 0.17-1.61, p = 0.258); however, high-grade loosening was associated with increased odds of hardware revision (OR 5.17, 95% CI 1.74-15.36, p = 0.003), including specifically surgery for correction of proximal junctional kyphosis (OR 5.73, 95% CI 1.27-25.95, p = 0.024). Among patients with PROMIS T-scores, those requiring hardware revision reported worse Pain Interference (65.0 ± 5.1 vs 59.6 ± 7.7, p = 0.001) and Physical Function (33.3 ± 5.6 vs 37.4 ± 7.4; p = 0.011). Patients with high-grade UIV loosening reported higher Oswestry Disability Index scores than those without high-grade loosening (grade 0 or 1), although this failed to reach statistical significance (44.0 ± 8.5 vs 33.7 ± 18.5, p = 0.101)., Conclusions: Grade 1 UIV pedicle screw loosening may represent a benign incidental finding, whereas high-grade loosening is associated with significantly increased odds of hardware revision surgery. High-grade loosening may also be associated with worse patient-reported disability. The authors' findings suggest that while low-grade UIV loosening may often be managed expectantly, identification of high-grade UIV pedicle screw loosening on follow-up imaging warrants increased attention and continued surveillance.

Purpose: This study aimed to investigate the relationship of preoperative hemoglobin levels as an independent prognostic factor for hospital and intensive care unit (ICU) length of stay (LOS) in patients undergoing surgery for adult spinal deformity (ASD), with the intent of determining whether there exists a correlation and enhancing patient preoperative optimization protocols., Methods: The authors reviewed consecutive patients who underwent elective thoracolumbosacral posterior spinal fusion (PSF) involving six or more vertebrae for ASD from January 1, 2013, to December 13, 2021, with a minimum follow-up period of two years. This study primarily investigated the association of preoperative hemoglobin levels with hospital and ICU LOS. To analyze the data, both unadjusted and adjusted generalized linear models (GLM), incorporating cubic splines for non-linear variables, were applied., Results: A total of 598 patients were included. GLMs for hospital and ICU LOS demonstrated nonlinear relationships with preoperative hemoglobin levels. Specifically, hospital LOS decreased with increasing preoperative hemoglobin until a significance threshold of 13.5 g/dl. Similarly, ICU LOS significantly decreased with increasing preoperative hemoglobin until 13.0 g/dl. Lower preoperative hemoglobin was associated with more perioperative transfusions, less likely discharge to home, and greater risk of reoperation., Conclusions: Preoperative anemia is an independent non-linear risk factor that significantly affects LOS, disposition, and outcomes after surgery for ASD. These findings advocate for a systemic preoperative approach and highlight the need for future research to improve postoperative outcomes and reduce hospital resource utilization., Level of Evidence: IV., (© 2024. The Author(s).)

Traumatic brain injury (TBI) often results in persistent learning and memory deficits, likely due to disrupted hippocampal circuitry underlying these processes. Precise temporal control of hippocampal neuronal activity is important for memory encoding and retrieval and is supported by oscillations that dynamically organize single unit firing. Using high-density laminar electrophysiology, we discovered a loss of oscillatory power across CA1 lamina, with a profound, layer-specific reduction in theta-gamma phase amplitude coupling in injured rats. Interneurons from injured animals were less strongly entrained to theta and gamma oscillations, suggesting a mechanism for the loss of coupling, while pyramidal cells were entrained to a later phase of theta. During quiet immobility, we report decreased ripple amplitudes from injured animals during sharp-wave ripple events. These results reveal deficits in information encoding and retrieval schemes essential to cognition that likely underlie TBI-associated learning and memory impairments, and elucidate potential targets for future neuromodulation therapies.

Traumatic brain injury (TBI) remains a pervasive clinical problem associated with significant morbidity and mortality. However, TBI remains clinically and biophysically ill-defined, and prognosis remains difficult even with the standardization of clinical guidelines and advent of multimodality monitoring. Here we leverage a unique data set from TBI patients implanted with either intracranial strip electrodes during craniotomy or quad-lumen intracranial bolts with depth electrodes as part of routine clinical practice. By extracting spectral profiles of this data, we found that the presence of narrow-band oscillatory activity in the beta band (12-30 Hz) closely corresponds with the neurological exam as quantified with the standard Glasgow Coma Scale (GCS). Further, beta oscillations were distributed over the cortical surface as traveling waves, and the evolution of these waves corresponded to recovery from coma, consistent with the putative role of waves in perception and cognitive activity. We consequently propose that beta oscillations and traveling waves are potential biomarkers of recovery from TBI. In a broader sense, our findings suggest that emergence from coma results from recovery of thalamo-cortical interactions that coordinate cortical beta rhythms., Competing Interests: Competing interests: the authors declare no competing interests.

Objective: Augmented reality (AR) is an emerging technology that may accelerate skill acquisition and improve accuracy of thoracolumbar pedicle screw placements. We aimed to quantify the relative assistance of AR compared with freehand (FH) pedicle screw accuracy across different surgical experience levels., Methods: A spine fellowship-trained and board-certified attending neurosurgeon, postgraduate year 4 neurosurgery resident, and second-year medical student placed 32 FH and 32 AR-assisted thoracolumbar pedicle screws in 3 cadavers. A cableless, voice-activated AR system was paired with a headset. Accuracy was assessed using χ 2 analysis and the Gertzbein-Robbins scale. Angular error, distance error, and time per pedicle screw were collected and compared., Results: The attending neurosurgeon had 91.6% (11/12) clinically acceptable (Gertzbein-Robbins scale A or B) insertion in both FH and AR groups; the resident neurosurgeon had 100% (9/9) FH and AR in both cases; the medical student had 72.3% (8/11) FH accuracy and 81.8% (9/11) AR accuracy. The medical student displayed significantly lower ideal (Gertzbein-Robbins scale A) FH accuracy compared with the resident neurosurgeon (P = 0.017) and attending neurosurgeon (P = 0.005), but no difference when using AR. FH screw placement was faster by both the attending neurosurgeon (median 46 seconds vs. 94.5 seconds, P = 0.0047) and the neurosurgery resident neurosurgeon (median 144 seconds vs. 140 seconds, P = 0.05). Total clinically acceptable AR and FH accuracy was 90.6% (29/32) and 87.5% (28/32), respectively (P = 0.69)., Conclusions: AR screw placement allowed an inexperienced medical student to double their accuracy in 1 training session. With subsequent iterations, this promising technology could serve as an important tool for surgical training., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Ewing's sarcoma is an uncommon, aggressive malignancy that typically presents as an osseous lesion, most commonly in children and adolescents. Very rarely Ewing's sarcoma can present as an intradural extramedullary mass mimicking more common tumors., Observations: A 32-year-old female had a left L3 nerve root-associated lesion identified in the setting of recent-onset radiculopathy. Contrast-enhanced magnetic resonance imaging of the lumbar spine was favored to demonstrate a schwannoma or neurofibroma. Hemilaminectomy, facetectomy, and resection of the mass led to improved radiculopathy and a tissue diagnosis of Ewing's sarcoma. Immediate referral to medical oncology facilitated expeditious initiation of adjuvant chemotherapy and radiation., Lessons: The differential diagnosis for newly identified nerve root-associated tumors should remain broad, including common benign pathologies and rare malignant entities. Tissue remains the gold standard for diagnosis, as preoperative imaging suggested a nerve sheath tumor. Malignant pathologies such as Ewing's sarcoma must be considered, especially in the setting of rapidly progressive symptoms or interval growth on serial imaging. Early diagnosis allows for the timely initiation of comprehensive oncological care. Long-term multidisciplinary follow-up is necessary for the surveillance of disease progression.

Objectives: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an immune-mediated neuroinflammatory disorder leading to demyelination of the CNS. Interleukin (IL)-6 receptor blockade is under study in relapsing MOGAD as a preventative strategy, but little is known about the role of such treatment for acute MOGAD attacks., Methods: We discuss the cases of a 7-year-old boy and a 15-year-old adolescent boy with severe acute CNS demyelination and malignant cerebral edema with early brain herniation associated with clearly positive serum titers of MOG-IgG, whose symptoms were incompletely responsive to standard acute therapies (high-dose steroids, IV immunoglobulins (IVIGs), and therapeutic plasma exchange)., Results: Both boys improved quickly with IL-6 receptor inhibition, administered as tocilizumab. Both patients have experienced remarkable neurologic recovery., Discussion: We propose that IL-6 receptor therapies might also be considered in acute severe life-threatening presentations of MOGAD., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: The optimal time to restart direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (NVAF) after traumatic intracranial hemorrhage (tICH) is unknown. Physicians must weigh the risk of recurrent hemorrhage against ischemic stroke. We investigated rates of stroke while holding anticoagulation, hemorrhage after anticoagulation resumption, and factors associated with the decision to restart anticoagulation., Methods: Patients presenting to our level I trauma center for tICH while on a DOAC for NVAF were retrospectively reviewed over 2 years. Age, sex, DOAC use, antiplatelet use, congestive heart failure, hypertension, age, diabetes, previous stroke, vascular disease, sex score for stroke risk in NVAF, injury mechanism, bleeding pattern, Injury Severity Score, use of a reversal agent, Glasgow Coma Scale at 24 hours, hemorrhage expansion, neurosurgical intervention, Morse Fall Risk, DOAC restart date, rebleed events, and ischemic stroke were recorded to study rates of recurrent hemorrhage and stroke, and factors that influenced the decision to restart anticoagulation., Results: Twenty-eight patients sustained tICH while on a DOAC. Fall was the most common mechanism (89.3%), and subdural hematoma was the predominant bleeding pattern (60.7%). Of the 25 surviving patients, 16 patients (64%) restarted a DOAC a median 29.5 days after tICH. One patient had recurrent hemorrhage after resuming anticoagulation. One patient had an embolic stroke after 118 days off anticoagulation. Age >80, Injury Severity Score ≥16, and expansion of tICH influenced the decision to indefinitely hold anticoagulation., Conclusion: The low stroke rate observed in this study suggests that holding DOACs for NVAF for 1 month is sufficient to reduce the risk of stroke after tICH. Additional data are required to determine optimal restart timing., Competing Interests: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 The Author(s).)

Regeneration after spinal cord injury (SCI) is limited by the presence of a glial scar and inhibitory cell signaling pathways that favor scar formation over regrowth of endogenous neurons. Tissue engineering techniques, including the use of allografted neural networks, have shown promise for nervous system repair in prior studies. Through the use of a minimally invasive injury model in rats, we describe the implantation of micro-tissue engineered neural networks (micro-TENNs) across a region of SCI, spanning the glial scar to promote axonal regeneration. Forty-three female Sprague-Dawley rats were included in this study. Micro-TENNs were preformed in vitro before implant, and comprised rat sensory dorsal root ganglion (DRG) neurons projecting long bundled axonal tracts within the lumen of a biocompatible hydrogel columnar encasement (1.2 cm long; 701 μm outer diameter × 300 μm inner diameter). Animals were injured using a 2F embolectomy catheter inflated within the epidural space. After a 2-week recovery period, micro-TENNs were stereotactically implanted across the injury. Animals were euthanized at 1 week and 1 month after implantation, and the tissue was interrogated for the survival of graft DRG neurons and outgrowth of axons. No intraoperative deaths were noted with implantation of the micro-TENNs to span the injury cavity. Graft DRG axons were found to survive at 1 week postimplant within the hydrogel encasement. Graft-derived axonal outgrowth was observed within the spinal cord up to 4.5 mm from the implant site at 1 month postinjury. Limited astroglial response was noted within the host, suggesting minimal trauma and scar formation in response to the graft. Micro-TENN sensory neurons survive and extend axons into the host spinal cord following a minimally invasive SCI in rats. This work serves as the foundation for future studies investigating the use of micro-TENNs as a living bridge to promote recovery following SCI. Impact statement As spinal cord injury pathology develops, the establishment of a glial scar puts an end to the hope of regeneration and recovery from the consequent neurological deficits. Therefore, growing attention is given to bioengineered scaffolds that can bridge the lesions bordered by this scar tissue. The utilization of longitudinally aligned preformed neural networks-referred to as micro-tissue engineered neural networks (TENNs)-presents a promising opportunity to provide a multipurpose bridging strategy that may take advantage of several potential mechanisms of host regeneration. In addition to providing physical support for regenerating spinal cord axons, micro-TENNs may serve as a functional "cable" that restores lost connections within the spinal cord.

Tentorial margin arteriovenous malformations (AVMs) at the cerebello-mesencephalic fissure are deep lesions, which can be safely resected via a lateral supracerebellar infratentorial approach. This video illustrates the case of a patient who presented with hemorrhage from a tentorial AVM. He was managed in the hybrid neurovascular operating room with Onyx (Medtronic) embolization of a superior cerebellar artery feeder followed by resection of the AVM, which included cerebellar relaxation from lumbar cerebrospinal fluid (CSF) drainage and lateral positioning. Wide cisternal arachnoid dissection at the quadrigeminal cistern allowed for a straight trajectory to the AVM without fixed retraction. Intraoperative transradial angiography confirmed complete AVM exclusion. This video was deemed Institutional Review Board (IRB) exempt by the University of Pennsylvania IRB as it is considered a case report, which does not require IRB approval or patient consent.  The patient consented to the procedure., (© Congress of Neurological Surgeons 2021.)

Damage to the microtubule lattice, which serves as a rigid cytoskeletal backbone for the axon, is a hallmark mechanical initiator of pathophysiology after concussion. Understanding the mechanical stress transfer from the brain tissue to the axonal cytoskeleton is essential to determine the microtubule lattice's vulnerability to mechanical injury. Here, we develop an ultrastructural model of the axon's cytoskeletal architecture to identify the components involved in the dynamic load transfer during injury. Corroborative in vivo studies were performed using a gyrencephalic swine model of concussion via single and repetitive head rotational acceleration. Computational analysis of the load transfer mechanism demonstrates that the myelin sheath and the actin/spectrin cortex play a significant role in effectively shielding the microtubules from tissue stress. We derive failure maps in the space spanned by tissue stress and stress rate to identify physiological conditions in which the microtubule lattice can rupture. We establish that a softer axonal cortex leads to a higher susceptibility of the microtubules to failure. Immunohistochemical examination of tissue from the swine model of single and repetitive concussion confirms the presence of postinjury spectrin degradation, with more extensive pathology observed following repetitive injury. Because the degradation of myelin and spectrin occurs over weeks following the first injury, we show that softening of the myelin layer and axonal cortex exposes the microtubules to higher stress during repeated incidences of traumatic brain injuries. Our predictions explain how mechanical injury predisposes axons to exacerbated responses to repeated injuries, as observed in vitro and in vivo., Competing Interests: The authors declare no competing interest.

Objective: We studied the risk of associated spinal and nonspinal injuries (NSIs) in the setting of observed thoracolumbar transverse process fracture (TPF) and examined the clinical management of TPF., Methods: Patients treated at a Level I trauma center over a 5-year period were screened for thoracolumbar TPF. Prevalence of associated spinal fractures and NSIs as well as relationship to level of TPF was explored. Clinical management and follow-up outcomes were reviewed., Results: A total of 252 patients with thoracolumbar TPFs were identified. NSIs were commonly observed (70.6%, n = 178); however, associated spinal fractures were more rarely seen (24.6%, n = 62, P < 0.0001). No patients had neurological deficits attributable to TPFs, and only 3 patients with isolated TPFs were treated with orthosis. Among patients with outpatient follow-up (70.6%, n = 178), none developed delayed-onset neurological deficits or spinal instability. Thoracic TPFs (odds ratio = 3.56, 95% confidence interval = 1.20-10.56) and L1 TPFs (odds ratio = 2.48, 95% confidence interval = 1.41-4.36) were predictive of associated thoracic NSIs. L5 TPF was associated with pelvic fractures (odds ratio = 6.30, 95% confidence interval = 3.26-12.17). There was no difference in rate of NSIs between isolated TPF (70.0%) and TPF with associated clinically relevant spinal fracture (72.6%, P = 0.70)., Conclusions: NSIs are nearly 3 times more common in patients with thoracolumbar TPFs than associated clinically relevant spinal fractures. Spine service consultation for TPF may be unnecessary unless fracture is associated with a clinically relevant spinal injury, which represents a minority of cases. However, detection of TPF should raise suspicion for high likelihood of associated NSIs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Current diagnostic criteria for the neuropathological evaluation of the traumatic brain injury-associated neurodegeneration, chronic traumatic encephalopathy, define the pathognomonic lesion as hyperphosphorylated tau-immunoreactive neuronal and astroglial profiles in a patchy cortical distribution, clustered around small vessels and showing preferential localization to the depths of sulci. However, despite adoption into diagnostic criteria, there has been no formal assessment of the cortical distribution of the specific cellular components defining chronic traumatic encephalopathy neuropathologic change. To address this, we performed comprehensive mapping of hyperphosphorylated tau-immunoreactive neurofibrillary tangles and thorn-shaped astrocytes contributing to chronic traumatic encephalopathy neuropathologic change. From the Glasgow Traumatic Brain Injury Archive and the University of Pennsylvania Center for Neurodegenerative Disease Research Brain Bank, material was selected from patients with known chronic traumatic encephalopathy neuropathologic change, either following exposure to repetitive mild (athletes n  = 17; non-athletes n  = 1) or to single moderate or severe traumatic brain injury ( n  = 4), together with material from patients with previously confirmed Alzheimer's disease neuropathologic changes ( n  = 6) and no known exposure to traumatic brain injury. Representative sections were stained for hyperphosphorylated or Alzheimer's disease conformation-selective tau, after which stereotypical neurofibrillary tangles and thorn-shaped astrocytes were identified and mapped. Thorn-shaped astrocytes in chronic traumatic encephalopathy neuropathologic change were preferentially distributed towards sulcal depths [sulcal depth to gyral crest ratio of thorn-shaped astrocytes 12.84 ± 15.47 (mean ± standard deviation)], with this pathology more evident in material from patients with a history of survival from non-sport injury than those exposed to sport-associated traumatic brain injury ( P  = 0.009). In contrast, neurofibrillary tangles in chronic traumatic encephalopathy neuropathologic change showed a more uniform distribution across the cortex in sections stained for either hyperphosphorylated (sulcal depth to gyral crest ratio of neurofibrillary tangles 1.40 ± 0.74) or Alzheimer's disease conformation tau (sulcal depth to gyral crest ratio 1.64 ± 1.05), which was comparable to that seen in material from patients with known Alzheimer's disease neuropathologic changes ( P  = 0.82 and P  = 0.91, respectively). Our data demonstrate that in chronic traumatic encephalopathy neuropathologic change the astroglial component alone shows preferential distribution to the depths of cortical sulci. In contrast, the neuronal pathology of chronic traumatic encephalopathy neuropathologic change is distributed more uniformly from gyral crest to sulcal depth and echoes that of Alzheimer's disease. These observations provide new insight into the neuropathological features of chronic traumatic encephalopathy that distinguish it from other tau pathologies and suggest that current diagnostic criteria should perhaps be reviewed and refined., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

While hippocampal-dependent learning and memory are particularly vulnerable to traumatic brain injury (TBI), the functional status of individual hippocampal neurons and their interactions with oscillations are unknown following injury. Using the most common rodent TBI model and laminar recordings in CA1, we found a significant reduction in oscillatory input into the radiatum layer of CA1 after TBI. Surprisingly, CA1 neurons maintained normal firing rates despite attenuated input, but did not maintain appropriate synchronization with this oscillatory input or with local high-frequency oscillations. Normal synchronization between these coordinating oscillations was also impaired. Simultaneous recordings of medial septal neurons known to participate in theta oscillations revealed increased GABAergic/glutamatergic firing rates postinjury under anesthesia, potentially because of a loss of modulating feedback from the hippocampus. These results suggest that TBI leads to a profound disruption of connectivity and oscillatory interactions, potentially disrupting the timing of CA1 neuronal ensembles that underlie aspects of learning and memory., (Copyright © 2020 Koch et al.)

Traumatic brain injury (TBI) is a risk factor for neurodegenerative disease, including chronic traumatic encephalopathy (CTE). Preliminary consensus criteria define the pathognomonic lesion of CTE as patchy tau pathology within neurons and astrocytes at the depths of cortical sulci. However, the specific tau isoform composition and post-translational modifications in CTE remain largely unexplored. Using immunohistochemistry, we performed tau phenotyping of CTE neuropathologies and compared this to a range of tau pathologies, including Alzheimer's disease, primary age-related tauopathy, ageing-related tau astrogliopathy and multiple subtypes of frontotemporal lobar degeneration with tau inclusions. Cases satisfying preliminary consensus diagnostic criteria for CTE neuropathological change (CTE-NC) were identified (athletes, n = 10; long-term survivors of moderate or severe TBI, n = 4) from the Glasgow TBI Archive and Penn Neurodegenerative Disease Brain Bank. In addition, material from a range of autopsy-proven ageing-associated and primary tauopathies in which there was no known history of exposure to TBI was selected as non-injured controls (n = 32). Each case was then stained with a panel of tau antibodies specific for phospho-epitopes (PHF1, CP13, AT100, pS262), microtubule-binding repeat domains (3R, 4R), truncation (Tau-C3) or conformation (GT-7, GT-38) and the extent and distribution of staining assessed. Cell types were confirmed with double immunofluorescent labelling. Results demonstrate that astroglial tau pathology in CTE is composed of 4R-immunoreactive thorn-shaped astrocytes, echoing the morphology and immunophenotype of astrocytes encountered in ageing-related tau astrogliopathy. In contrast, neurofibrillary tangles of CTE contain both 3R and 4R tau, with post-translational modifications and conformations consistent with Alzheimer's disease and primary age-related tauopathy. Our observations establish that the astroglial and neurofibrillary tau pathologies of CTE are phenotypically distinct from each other and recapitulate the tau immunophenotypes encountered in ageing and Alzheimer's disease. As such, the immunohistochemical distinction of CTE neuropathology from other mixed 3R/4R tauopathies of Alzheimer's disease and ageing may rest solely on the pattern and distribution of pathology., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Diffuse axonal injury (DAI) is an important consequence of traumatic brain injury (TBI). At the moment of trauma, axons rarely disconnect, but undergo cytoskeletal disruption and transport interruption leading to protein accumulation within swellings. The amyloid precursor protein (APP) accumulates rapidly and the standard histological evaluation of axonal pathology relies upon its detection. APP+ swellings first appear as varicosities along intact axons, which can ultimately undergo secondary disconnection to leave a terminal "axon bulb" at the disconnected, proximal end. However, sites of disconnection are difficult to determine with certainty using standard, thin tissue sections, thus limiting the comprehensive evaluation of axon degeneration. The tissue-clearing technique, CLARITY, permits three-dimensional visualization of axons that would otherwise be out of plane in standard tissue sections. Here, we examined the morphology and connection status of APP+ swellings using CLARITY at 6 h, 24 h, 1 week and 1 month following the controlled cortical impact (CCI) model of TBI in mice. Remarkably, many APP+ swellings that appeared as terminal bulbs when viewed in standard 8-µm-thick regions of tissue were instead revealed to be varicose swellings along intact axons when three dimensions were fully visible. Moreover, the percentage of these potentially viable axon swellings differed with survival from injury and may represent the delayed onset of distinct mechanisms of degeneration. Even at 1-month post-CCI, ~10% of apparently terminal bulbs were revealed as connected by CLARITY and are thus potentially salvageable. Intriguingly, the diameter of swellings decreased with survival, including varicosities along intact axons, and may reflect reversal of, or reduced, axonal transport interruption in the chronic setting. These data indicate that APP immunohistochemistry on standard thickness tissue sections overestimates axon disconnection, particularly acutely post-injury. Evaluating cleared tissue demonstrates a surprisingly delayed process of axon disconnection and thus longer window of therapeutic opportunity than previously appreciated. Intriguingly, a subset of axon swellings may also be capable of recovery., (© 2018 International Society of Neuropathology.)

Although millions of individuals suffer a traumatic brain injury (TBI) worldwide each year, it is only recently that TBI has been recognized as a major public health problem. Beyond the acute clinical manifestations, there is growing recognition that a single severe TBI (sTBI) or repeated mild TBIs (rTBI) can also induce insidious neurodegenerative processes, which may be associated with early dementia, in particular chronic traumatic encephalopathy (CTE). Identified at autopsy examination in individuals with histories of exposure to sTBI or rTBI, CTE is recognized as a complex pathology featuring both macroscopic and microscopic abnormalities. These include cavum septum pellucidum, brain atrophy and ventricular dilation, together with pathologies in tau, TDP-43, and amyloid-β. However, the establishment and characterization of CTE as a distinct disease entity is in its infancy. Moreover, the relative "dose" of TBI, such as the frequency and severity of injury, associated with risk of CTE remains unknown. As such, there is a clear and pressing need to improve the recognition and diagnosis of CTE and to identify mechanistic links between TBI and chronic neurodegeneration.

Repetitive mild traumatic brain injury (mTBI) is implicated in chronic neurological illness. The development of animal models of repetitive mTBI in mice is essential for exploring mechanisms of these chronic diseases, including genetic vulnerability by using transgenic backgrounds. In this study, the rat model of impact acceleration (IA) was redesigned for the mouse cranium and used in two clinically relevant repetitive mTBI paradigms. We first determined, by using increments of weight dropped from 1m that the 40g weight was most representative of mTBI and was not associated with fractures, brain contusions, anoxic-ischemic injury, mortality, or significant neurological impairments. Quantitative evaluation of traumatic axonal injury (TAI) in the optic nerve/tract, cerebellum and corpus callosum confirmed that weight increase produced a graded injury. We next evaluated two novel repetitive mTBI paradigms (1 time per day or 3 times per day at days 0, 1, 3, and 7) and compared the resulting TAI, neuronal cell death, and neuroinflammation to single hit mTBI at sub-acute (7days) and chronic time points (10weeks) post-injury. Both single and repetitive mTBI caused TAI in the optic nerve/tract, cerebellum, corticospinal tract, lateral lemniscus and corpus callosum. Reactive microglia with phagocytic phenotypes were present at injury sites. Severity of axonal injury corresponded to impact load and frequency in the optic nerve/tract and cerebellum. Both single and repeat injury protocols were associated with retinal ganglion cell loss and optic nerve degeneration; these outcomes correlated with impact load and number/frequency. No phosphorylated tau immunoreactivity was detected in the brains of animals subjected to repetitive mTBI. Our findings establish a new model of repetitive mTBI model featured by TAI in discrete CNS tracts, especially the visual system and cerebellum. Injury in retina and optic nerve provides a sensitive measure of severity of mTBI, thus enabling further studies on mechanisms and experimental therapeutics. Our model can also be useful in exploring mechanisms of chronic neurological disease caused by repetitive mTBI in wild-type and transgenic mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Chronic traumatic encephalopathy (CTE) is associated with repetitive mild traumatic brain injury (mTBI) in the context of contact and collision sports, but not all exposed individuals develop this condition. In addition, experiments in animal models in several laboratories have shown that non-transgenic mice do not develop tauopathy after exposure to repetitive mTBI schedules. It is thus reasonable to assume that genetic factors may play an etiological role in the development of CTE. More than 40 mutations in the tau gene are known to confer proneness to aggregation and are thought to cause neurodegenerative diseases including frontotemporal degeneration (FTD). Transgenic mice harboring these mutations can be used to ask the question whether repetitive mTBI can accelerate onset and course of tauopathy or worsen the outcomes of transgenic disease. In this study, we exposed mice harboring the tau P301S transgene associated with FTD to repetitive mTBI schedules by impact acceleration (IA) that we have previously characterized. We explored the progression of tauopathy in the retina and neocortex based on density of neuronal profiles loaded with tau pS422, a marker of advanced tau hyperphosphorylation. We found that the density of tau pS422 (+) retinal ganglion cells (RGCs) increased twenty fold with one mTBI hit, a little over fifty fold with four mTBI hits and sixty fold with 12 mTBI hits. The severity of mTBI burden (number of hits) was a significant factor in tauopathy outcome. On the other hand, we found no association between repetitive mTBI and density of pS422 (+) neuronal profiles in neocortex, a region that is not featured by significant TAI in our repetitive mTBI model. We observed similar, but less prominent, trends in tauopathy-prone transgenic mice harboring all 6 isoforms of wild-type human tau without mouse tau. Our findings indicate that repetitive mTBI accelerates tauopathy under diverse genetic conditions predisposing to tau aggregation and suggest a vulnerability-stress model in understanding some cases of acquired neurodegenerative disease after repetitive mTBI., (Copyright © 2015 Elsevier Inc. All rights reserved.)

There is a growing concern regarding the propensity of second generation antipsychotics (SGAs) to induce weight gain and metabolic adverse effects. Recent consensus guidelines have recommended assessment and monitoring procedures to appropriately detect and manage these adverse effects. This study addresses the appreciation and readiness of clinicians to implement management guidelines for these adverse effects. Respondents indicated awareness of the risks of treatment with SGAs. The extent of monitoring for metabolic adverse effects was low and inconsistent across measures and in frequency of evaluation. Ongoing efforts are needed to support and encourage change in clinician practice.

Headache is a common complaint. Psychological treatment has been effective in managing the symptoms of vascular (migraine and combined migraine-tension) headache. Traditional office-based treatment may be inconvenient for many patients in terms of time and travel constraints, thereby limiting access. Telemedicine has emerged as a promising delivery medium to address these barriers to access. However, the efficacy of remotely delivered treatment for vascular headache remains untested. This case series is a preliminary evaluation of effectiveness and feasibility of an analogue telemedicine system for delivery of psychophysiological treatment for vascular headache. Three of four subjects showed improvement. These findings are encouraging for follow-up study of the clinical utility and broader viability of headache treatment via distance technology.

Many of the techniques and skills the average front-line practitioner possesses (such as intake, psychological testing, cognitive behavior therapy, and relaxation therapy) can be readily and effectively applied to a chronic-pain population. More specialized techniques for pain reduction, such as biofeedback training, can be easily learned by the generalist clinician with a minimum of additional training. In this article, four general steps to assess and reduce chronic pain are reviewed. Through careful use of the available research literature, and by consulting with a colleague who has expertise in chronic pain, most psychologists can straightforwardly begin to help individuals suffering from chronic pain., (Copyright 2002 Wiley Periodicals, Inc.)

Surface electromyographic (EMG) activity recordings of bilateral paraspinal muscle tension were measured twice on 20 non-pain controls and on 46 low back pain subjects (21 individuals with intervertebral disk disorders and 25 subjects with unspecified musculoskeletal backache) during 6 positions: standing, bending from the waist, rising, sitting with back unsupported, sitting with back supported, and prone. Back pain subjects were measured during both low pain and high pain states. Results revealed a non-significant trend for all subjects, regardless of diagnosis, to have higher paraspinal muscle tension levels on the second (or high pain) assessment. A significant diagnosis by position interaction was observed which was similar to the interaction in our previous study which employed only a single measurement session. Analysis of simple main effects revealed this to be due to control subjects during the standing position having lower EMG levels than the back pain groups, and intervertebral disk disorder subjects having higher EMG levels than the other groups during the supported sitting position. As in our previous study, diagnosis was found to be a clinically significant factor, in that controls had much fewer clinically abnormal readings than back pain patients. The lack of a significant effect for pain state is congruent with findings in the headache literature. The importance of clearly defined diagnostic categories in low back pain research and the utility of measuring subjects in various positions is discussed, as are possible explanations for lack of significant pain state findings.

Surface EMG recordings of bilateral paraspinal muscle tension were measured on 207 subjects (29 non-back pain controls, 20 individuals with spondyloarthritis, 52 with intervertebral disk disorders, 66 with unspecified musculoskeletal backache, 17 with some combination of the above 3 groups and 23 subjects with other types of back pain, including unknown, scoliosis and psychogenic) in 6 positions: standing, bending from the waist, rising, sitting with back unsupported, sitting with back supported and prone. Results of both individual and group analyses revealed a significant main effect of diagnosis. Post hoc analyses (Duncan's) revealed controls to have significantly lower overall EMG levels than the intervertebral disk disorders and unspecified musculoskeletal backache groups. A significant diagnosis by position interaction was observed. Analysis of simple main effects revealed this to be due primarily to control subjects during the standing position having lower EMG levels than all other groups, and intervertebral disk disorder subjects having higher EMG levels than all other groups during the supported sitting position. The importance of clearly defined diagnostic categories in low back pain research and the utility of measuring subjects in various positions are discussed.